Fucosyltransferase VII-Deficient Mice with Defective E-, P-, and L-Selectin Ligands Show Impaired CD4+ and CD8+ T Cell Migration into the Skin, but Normal Extravasation into Visceral Organs

Fucosyltransferase-IV and -VII double knockout (FtDKO) mice reveal profound impairment in T cell trafficking to lymph nodes (LNs) due to an inability to synthesize selectin ligands. We observed an increase in the proportion of memory/effector (CD44high) T cells in LNs of FtDKO mice. We infected FtDKO mice with lymphocytic choriomeningitis virus to generate and track Ag-specific CD44highCD8 T cells in secondary lymphoid organs. Although frequencies were similar, total Ag-specific effector CD44highCD8 T cells were significantly reduced in LNs, but not blood, of FtDKO mice at day 8. In contrast, frequencies of Ag-specific memory CD44highCD8 T cells were up to 8-fold higher in LNs of FtDKO mice at day 60. Because wild-type mice treated with anti-CD62L treatment also showed increased frequencies of CD44high T cells in LNs, we hypothesized that memory T cells were preferentially retained in, or preferentially migrated to, FtDKO LNs. We analyzed T cell entry and egress in LNs using adoptive transfer of bone fide naive or memory T cells. Memory T cells were not retained longer in LNs compared with naive T cells; however, T cell exit slowed significantly as T cell numbers declined. Memory T cells were profoundly impaired in entering LNs of FtDKO mice; however, memory T cells exhibited greater homeostatic proliferation in FtDKO mice. These results suggest that memory T cells are enriched in LNs with T cell deficits by several mechanisms, including longer T cell retention and increased homeostatic proliferation.

Section: Discussioncontrasting

confidence: 44%

Memory T Cells Are Enriched in Lymph Nodes of Selectin-Ligand–Deficient Mice

Harp

Gilchrist

Onami

2010

“…In this study, we showed that despite the absence of the IL-12R␤2 chain on resting Th2 cells (data not shown), these Th2 cells immediately up-regulate IL-12R␤2 chain upon activation, and consequently respond to IL-12 as IL-12R ligation induced the expression of the E-selectin ligand CLA and ␣(1-3)-FucTVII. FucTVII mediates the final and most selective step of posttranslational glycosylations of E-selectin ligands, and it was shown that FucTVII Ϫ/Ϫ Th1, and Th2 cells are unable to home to the skin (9,(41)(42)(43)(44)(45). Even though there is evidence that alternative factors may regulate cutaneous imprinting (4,46), our data demonstrate that IL-12 is sufficient to potently regulate skin homing in T cells.…”

Section: Discussionmentioning

confidence: 58%

IL-12 Instructs Skin Homing of Human Th2 Cells

Biedermann

Lametschwandtner

Tangemann

et al. 2006

Distinct pattern of homing receptors determines the tissue preference for T cells to exert their effector functions. This homing competence is mostly determined early during T cell activation of naive T cells. In contrast, mechanisms governing the acquisition of particular homing receptors by T cells of the memory phenotype remain enigmatic. Th2 cell-mediated allergic diseases tend to flare during infections despite that these infections prime APCs to produce the prototypic Th1 cell-differentiating cytokine IL-12. In this study, we investigate the effect of IL-12 on the regulation of cutaneous lymphocyte Ag (CLA) on differentiated Th2 cells and consequences of this expression for allergic inflammation. Upon activation with IL-12, CLA− Th2 cells rapidly up-regulated IL-12Rβ2 chain, α(1-3)-fucosyltransferase VII, and CLA molecules. IL-12-mediated CLA expression on Th2 cells was functional because it mediated rolling of these Th2 cells on E-selectin in vitro and migration into human skin grafts in SCID mice. CLA induction occurred immediately after exposure to IL-12 and was independent of IFN-γ expression. In accordance, the transcription factor mediating IFN-γ expression, T-bet, does not directly affect CLA expression. However, CLA expression was further enhanced after IL-12 treatment of T-bet+-transfected Th2 cells in agreement with an increased IL-12 responsiveness of these cells caused by T-bet. The finding that IL-12 conferred skin-homing potential to already differentiated Th2 cells before inducing a switch in their cytokine production profile may explain the observed exacerbation of allergic skin diseases following bacterial infections.

“…Ag-specific cutaneous DTH to an infectious agent, lymphocytic choriomeningitis virus (LCMV), also depends on FucT-VII (28). However, since DTH reactions were only delayed after LCMV infection of FucT-VII Ϫ/Ϫ mice (29), showing a retarded extravasation of CD4 ϩ and CD8 ϩ T cells into the skin, FucT-IV has been inferred to direct a low degree of residual E-and P-selectin ligand expression by activated T cells (14), similar to its function in neutrophils (13). In this study, we report that the DTH response in M. tuberculosis-infected mice is strictly dependent on FucT-VII, with little or no contribution of FucT-IV activity.…”

Section: Discussionmentioning

confidence: 99%

Selectin Ligand-Independent Priming and Maintenance of T Cell Immunity during Airborne Tuberculosis

Schreiber

Ehlers

Aly

et al. 2006

Self Cite

Immunity to Mycobacterium tuberculosis infection is critically dependent on the timely priming of T effector lymphocytes and their efficient recruitment to the site of mycobacterial implantation in the lung. E-, P-, and L-selectin counterreceptors control lymphocyte homing to lymph nodes and leukocyte trafficking to peripheral sites of acute inflammation, their adhesive function depending on fucosylation by fucosyltransferases (FucT) IV and VII. To address the relative importance of differentially glycosylated selectin counterreceptors for priming of T cell effector functions in a model of mycobacteria-induced granulomatous pulmonary inflammation, we used aerosol-borne M. tuberculosis to infect FucT-IV−/−, FucT-VII−/−, FucT-IV−/−/FucT-VII−/−, or wild-type control mice. In lymph nodes, infected FucT-IV−/−/FucT-VII−/− and, to a lesser extent, FucT-VII−/− mice had severely reduced numbers of T cells and reduced Ag-specific effector responses. By contrast, recruitment of activated T cells into the lungs was similar in all four groups of mice during infection and expression of T cell, and macrophage effector functions were only delayed in lungs of FucT-IV−/−/FucT-VII−/− mice. Importantly, lungs from all groups expressed CXCL13, CCL21, and CCL19 and displayed organized follicular neolymphoid structures after infection with M. tuberculosis, which suggests that the lung served as a selectin ligand-independent priming site for immune responses to mycobacterial infection. All FucT-deficient strains were fully capable of restricting M. tuberculosis growth in infected organs until at least 150 days postinfection. Our observations indicate that leukocyte recruitment functions dictated by FucT-IV and FucT-VII-dependent selectin ligand activities are not critical for inducing or maintaining T cell effector responses at levels necessary to control pulmonary tuberculosis.